For patients with cervical cancer that has recurred after treatment or has spread elsewhere in the body, adding the experimental drug cediranib to standard chemotherapy improves tumour shrinkage and adds a modest improvement in progression-free survival, researchers report at the ESMO 2014 Congress in Madrid.
In Europe, about 70% of patients with cervical cancer are cured by either surgery or chemo-radiotherapy. Those patients with recurrent or secondary cancer have a very poor outlook. Only about 20-30% have tumour shrinkage after conventional chemotherapy and survival is usually less than one year.
In the phase II CIRCCa trial, researchers compared two groups of patients with relapsed or metastatic cervical cancer given conventional chemotherapy with carboplatin and paclitaxel plus either cediranib (34 patients) or an identical looking placebo tablet (35 patients).
"Cervical cancers with a well-developed blood supply can have a particularly bad outcome. The experimental drug cediranib blocks the cell surface receptor VEGF, which stimulates the growth of new blood vessels to feed the growth of tumours," explains study researcher Dr Paul Symonds, of the Department Cancer Studies & Molecular Medicine at the University of Leicester, UK.
In the study, patients who received cediranib in addition to chemotherapy had greater tumour shrinkage than those treated by chemotherapy plus placebo (66% versus 42%). There was also a modest but statistically significant increase in median progression-free survival (35 versus 30 weeks). There was no statistically significant difference in median overall survival.
One month into treatment, VEGF receptor 2 levels in blood were more likely to be reduced in cediranib group (median change in log10 VEGFR-2 from baseline 0.036 versus 0.067).
Targeting the tumour blood supply seems to be a promising way to increase the effectiveness of chemotherapy in cervical cancer, Symonds says. "Recurrent or metastatic cervix cancer is really difficult to treat with a low response rate and poor survival. This study has opened up a new avenue of investigation for a difficult-to-treat cancer."
The researchers are now conducting an individual patient analysis to correlate response to chemotherapy with the fall in VEGFR receptor levels in the blood. They are also looking at other tumour biomarkers that may have been reduced by cediranib.
Commenting on the study, Dr Andres Poveda, Head of the Gynecological Oncology Clinic at Fundación Instituto Valenciano de Oncología, Valencia, Spain, who was not involved in the research, said the CIRCCa study is the second recent trial to show the benefit of adding an antiangiogenic drug to chemotherapy in cervical cancer.
"The impact on progression-free survival is important, and other trial objectives were reached, such as response rate," Poveda said.
Poveda also noted that recent years have been positive for the treatment of cervical cancer. "For two decades, advances in treatment for patients with advanced cervical cancer had been slow and scarce," he said. "Between 1989 and 2009, modifications of chemotherapy regimens resulted in an increased survival rate of just four months. Then the first study to include an antiangiogenic drug, bevacizumab, obtained spectacular results, offering a survival benefit of four months in one study - which is the equivalent to that obtained over the previous 20 years."
"The FDA recently approved the use of bevacizumab as it completely changed clinical practice," Poveda added. "We are now waiting for phase III results to confirm the favorable predictions of this treatment with cediranib."
CIRCCa: A randomised double blind phase II trial of carboplatin-paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cervical cancer. (CRUK Grant Ref: C1256/A11416), P. Symonds, C. Gourley, S. Davidson, C. West, C. Dive, J. Paul, K. Carty, E. McCartney, D. Rai, S. Banerjee, D. Jackson, R. Lord, M. McCormack, E. Hudson, N. Reed, M. Flubacher, P. Jankowska, M. Powell.
Aim: Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly (response rates 20-30%) to conventional chemotherapy with an overall survival of less than a year. High tumour angiogenesis along with high levels of intratumoural vascular endothelial growth factor (VEGF) are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGF receptors1,2&3.
Methods: Patients were randomised (1:1) to receive carboplatin AUC5 + paclitaxel 175mg/m2 3 weekly for a maximum of 6 cycles plus 20mg cediranib daily (arm A) or placebo (arm P) until disease progression. Plasma VEGFR-2 levels were measured at baseline and at 28 days into chemotherapy. The primary end-point was progression- free survival(PFS). Secondary end-points included changes in sVEGFR-2 from baseline to day 28, overall survival (OS), response, toxicity and quality of life. The study has approximately 80% power (20% 1-sided) to detect a 60% increase in median PFS from 4 to 6.4 months.
Results: 69 patients were randomised (35 P; 34 A) during 2010-12, 13% with local relapse only, 30% with extra pelvic metastases and 57% with both. 83% had 1 line of previous treatment. 79% completed 6 cycles of chemotherapy. 22% stopped P and 17% stopped A for treatment related reasons. Median PFS (wks; 80% CI) is 30 (29, 31) on P versus 35 (32, 38) on A (hazard ratio A/P [HR] 0.61; 80% CI: (0.41, 0.89); P = 0.046). Median change in log10 sVEGFR-2 from baseline was .067 (n=22) on P compared to -.036 (n=18) on A (P<.001 median os was wks for p versus a ci: overall response rate and on more patients experienced grade diarrhoea v href="/articles/150109.php" title="Hypertension: Causes, Symptoms and Treatments" class="keywords">hypertension (34% v 12%, p=.038). During the drug only period 9% of P patients experienced grade 2/3/4 toxicity compared to 19% on A.
Conclusions: PFS, inhibition of VEGFR-2 receptor and response rate were all significantly increased on arm A. This was accompanied by a manageable toxicity increase (diarrhoea and hypertension). Acknowledgements: This research was supported by CRUK,ECMC funding and conducted with support from Investigator-Sponsored Study Collaboration between AstraZeneca and the NCRN. Study Sponsors: NHS Greater Glasgow & Clyde and University of Glasgow.
Disclosure: C. Gourley: Personal (advisory board membership) and non-personal specific and non-specific interests in AstraZeneca, GlaxoSmithKline and Roche; S. Banerjee: Conflict of Interest - AstraZeneca (not directly financially remunerated); R. Lord: Has acted on advisory boards for AstraZeneca but not in relation to Cediranib. All other authors have declared no conflicts of interest.